Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS), characterized by immune cell infiltration, demyelination and neuroaxonal damage. Remyelination is the generation of new myelin sheaths after injury; it occurs spontaneously in animal demyelinating models and human disease but the majority of lesions in MS patients fail to completely remyelinate.
In addition to providing rapid saltatory conduction of action potentials, myelin provides axons a source of metabolites for their general wellbeing; indeed, chronic demyelinated axons are more prone to irreversible damage and loss. It is therefore necessary to develop strategies to promote remyelination when it fails in MS and other demyelinating disorders.
For remyelination to occur, oligodendrocyte precursor cells (OPCs), which are situated throughout the adult CNS and are capable of making and remodelling myelin throughout the lifespan, must first proliferate and migrate into demyelinating lesions; subsequent maturation into oligodendrocytes, involving the extension of processes that contact, enwrap and compact around axons complete the remyelination program.
The cause of remyelination failure is likely several-fold and includes lesion-associated factors that impede any of the aforementioned steps. These inhibitory cues include Wnt and Notch signalling pathways, semaphorins, Lingo-1, myelin debris, as well as extracellular matrix (ECM) molecules such as hyaluronan and chondroitin sulfate proteoglycans (CSPGs).
CSPGs are a family of large molecules consisting of a single protein backbone tethered to few or many repeating disaccharide (glucuronic acid and N-acetyl-galactosamine) polymers called chondroitin sulfate. Further heterogeneity of CSPG structure results from several sulfation sites by different enzymes on each disaccharide pair. CSPGs, which act as guidance and signalling molecules during development, maintain the structural integrity of the healthy CNS in specialized structures such as basement membranes, perineuronal nets and nodes of Ranvier.
In the damaged CNS, CSPGs become highly upregulated as part of the astrogliotic scar, and are potent inhibitors of axon regeneration after traumatic injury. Several approaches to neutralize CSPGs after injury have included digestion of CSPGs with the enzyme chondroitinase ABC, RNA interference of chain polymerization enzymes, and peptide blocking of protein tyrosine phosphatase sigma, one of the recently characterized CSPG receptors.
A number of CSPG members are upregulated in MS lesions, including versican, aggrecan and neurocan. Various researchers have previously shown that CSPGs inhibit morphological differentiation of OPCs in vitro and remyelination in vivo.
Researchers in the journal Nature Communications attempt two strategies to overcome the inhibitory nature of CSPGs on OPC growth: first, to screen for drugs that permit OPCs to grow in the presence of inhibitory CSPGs, and second, to test the efficacy of a small molecule CSPG synthesis inhibitor in novel applications to the CNS.
Authors show that in vitro, OPCs have dramatically reduced process outgrowth in the presence of CSPGs, and a medication library that includes a number of recently reported OPC differentiation drugs failed to rescue this inhibitory phenotype on CSPGs. They introduce a novel CSPG synthesis inhibitor to reduce CSPG content and find rescued process outgrowth from OPCs in vitro and accelerated remyelination following focal demyelination in mice.
Preventing CSPG deposition into the lesion microenvironment may be a useful strategy to promote repair in multiple sclerosis and other neurological disorders.
Inhibiting proteoglycan synthesis to promote remyelination
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